# Mechanisms of Acquired Resistance to PD-L1-Targeted Therapy in Cancer

> **NIH NIH F30** · ROSWELL PARK CANCER INSTITUTE CORP · 2021 · $31,538

## Abstract

Project Summary
The clinical use of immune checkpoint inhibitors (ICIs) that target the programmed cell death protein 1 (PD-1)
and its ligand PD-L1 have significantly improved outcomes in patients with numerous cancer types. However, a
large proportion of patients eventually relapse on therapy. Currently, preclinical studies of acquired resistance
to ICIs have been limited because most tumor models do not faithfully mimic treatment failure as it occurs in
patients. This gap has limited the understanding of resistance mechanisms that are urgently needed to identify
optimal second-line treatments. In several cancer types, receptor tyrosine kinase inhibitors (RTKIs) that target
metastasis and angiogenesis pathways are being tested for efficacy after anti-PD-L1 (αPD-L1) treatment
failure. Currently, there is no method to identify who will respond. Here, we propose that intracellular functions
of PD-L1 may be the key to determining RTKI responses after ICI failure. PD-L1 has cytoplasmic domains that
can control various signaling pathways but these functions have not been tested in models of resistance. We
have preliminary data that suggest αPD-L1 treatment failure can induce secretory changes controlled by IFNβ
which, in turn are regulated by intracellular PD-L1 signaling. Notably, we also found that PD-L1 treatment can
confer a cross-resistance to RTKIs. The overall hypothesis of this research is that resistance to PD-L1
inhibition can enhance IFNβ-mediated secretory profiles through intracellular PD-L1 signaling which, in turn,
can reduce the efficacy of RTKIs. To test this, we first propose to investigate the effects of chronic PD-L1
treatment on intracellular functions regulating IFN-β mediated secretory changes (Aim 1). This work will be
conducted using novel mouse tumor models of acquired αPD-L1 treatment resistance developed in our
laboratory. Next, we will test whether IFNβ signaling inhibition may improve the efficacy of RTKI treatments
(including cabozantinib and axitinib) in αPD-L1 treatment-refractory models (Aim 2). Together, these studies
aim to identify a novel role for IFNβ signaling in αPD-L1 treated tumor cells with the goal of improving second-
line treatment options in patients.

## Key facts

- **NIH application ID:** 10114896
- **Project number:** 5F30CA243281-02
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** YUHAO SHI
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,538
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114896

## Citation

> US National Institutes of Health, RePORTER application 10114896, Mechanisms of Acquired Resistance to PD-L1-Targeted Therapy in Cancer (5F30CA243281-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114896. Licensed CC0.

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